Neuroscience

Rett syndrome and neurodevelopmental disorders

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Group leader

Nicoletta Landsberger

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Since the beginning of her research activity, NL main interests were in chromatin structure and epigenetics and their influence on gene expression. Thereby, in the last period of her Post-Doc activity in dr. Wolffe’s lab (NIH/USA), she got interested on DNA methylation and MeCP2. At that time the protein was very little characterized and was still not recognized as the main cause of Rett syndrome. The interest on MeCP2 was reinforced by the discovery in 1999 of its association with Rett syndrome and other neurological disorders. Since then, she focused the lab research on a better characterization of the methyl binding protein, studying its partners, its phosphorylation and the molecular consequences of its deficiency. In the last years, she moved her research forward, including preclinical studies. These studies have brought to 26 original papers, 3 invited reviews, 1 commentary and 1 chapter of book edited by Elsevier.

Eventually, because of the interest in MeCP2 phosphorylation, she initiated a study aimed at identifying the involved kinases. Obtained results led NL to focus part of her studies on CDKL5, an X-linked gene responsible of a severe neurodevelopmental disorder mainly affecting females and partly resembling to a variant form of Rett syndrome. Obtained results have led to  19 papers on CDKL5, that overall have largely contributed to the current knowledge of CDKL5 activity and regulation.

Scopus Res. ID:6603941648

ORCID ID: https://orcid.org/0000-0003-0820-3155

Research activity

General research

Our research activity focuses on neurodevelopmental diseases, with a particular attention to those caused by mutations in MECP2. To date, there is no cure for these diseases and patients are mainly treated with drugs for core symptoms. This is partly due to an insufficient knowledge of the pathogenic mechanisms, as well as to a complexity of the altered biological processes. Our research aims at identifying the molecular and cellular defects underlying these diseases, and in particular Rett syndrome (RTT), in order to identify new therapeutic targets and biomarkers useful for studying the progression of the disease. Further, we are testing innovative molecular and cellular approaches for the treatment of RTT. Our research mainly uses transgenic mouse models mutated in Mecp2 (or Cdkl5), and primary cultured neurons. Obtained results are validated in mutated human cells.

Current main projects

Identification and characterization of new modifier genes of Rett syndrome

Mutations in MECP2 cause deregulation of a large number of genes. Alterations of some of these could contribute to typical neurobiological defects of RTT; their identification could lead to a better comprehension of the disease and/or the identification of new therapeutic targets.

We have recently distinguished some genes consistently altered both in cellular and animal models of RTT, and in patients. According to their functions, we have initiated projects aiming at characterizing, through approaches of molecular and cellular biology, their involvement in experimental models of the disease, as well as in physiological conditions, if the information available is limited.

New therapeutic approaches for Rett syndrome

Based on our recent publications or literature evidence, we are evaluating the effectiveness of new molecular and pharmacological approaches for the treatment of Rett syndrome. Amelioration of typical molecular and behavioral phenotypes is tested in mouse models of Mecp2 and in cells derived from RTT patients.

Characterization of the molecular mechanisms responsible for the benefits exerted by staminal cell transplantation In Rett syndrome

We have recently found that NPC transplantation in the Mecp2 KO mouse brain significantly slows down the progression of symptoms, alleviating its severity. Through multiple cellular and molecular biology approaches, we aim at isolating the molecular mechanisms activated by transplanted cells, which could reveal new therapeutic approaches.